Identification of both MHC class I and II restricted antigens has provided opportunities to develop more effective cancer vaccines, however, current immunotherapy strategies with tumor antigens are relatively ineffective and have not produced compelling evidence of any durable therapeutic benefits. Recent studies suggest that inflammatory Th17 cells and innate immunity at tumor sites may promote rather than inhibit cancer development and progression. Moreover, CD4+ regulatory T (Treg) cells at tumor sites potently suppress the CD4+ and CD8+ T-cell responses elicited by vaccination, thus promoting tumor growth. These studies suggest that understanding of the interplay between immune cells and tumor cells is a critical step to develop more effective cancer therapy. The underlying rationale is that inflammation is a major driving force in the pathogenesis of many types of cancer, including colorectal cancer and viral infection-associated malignancies. The delicate and dynamic balance among antitumor immunity, inflammatory CD4+ Th17 cells and immune suppressive cells may be important factor in tumor elimination, development and progression. Despite the importance of inflammatory cytokines and CD4+ Th17 cells in cancer, their role and regulatory mechanisms in cancer remain controversial. We therefore hypothesize that innate immune signaling is critical in the control of inflammation, which in turn modulates adaptive immunity and CD4+ Th17 cell differentiation. Thus, identification of key innate immune signaling molecules that control inflammation and Th17 differentiation will be critical for us to define the role of inflammation and Th17 cells in inflammation-associated cancer development and to dissect molecular mechanisms by which inflammatory cytokines and Th17 cells directly or indirectly modulate tumor development. To test our central hypothesis, we propose three aims: 1) To determine whether NLRC5 and TAK1 can modulate key proinflammatory cytokines and Th17 cells in vivo; 2) To define the function of inflammatory cytokines and Th17 cells in cancer development; 3) To enhance antitumor immunity by manipulating innate signaling molecules, Th17 and Treg cells. A favorable outcome would open new opportunities for treating cancer and other immune diseases through regulating these inflammation and subsets of CD4+ T cells.